T cell activation is orchestrated by a cosignaling network, which is involved in all stages of the T cell response. The B7/CD28 family of immunoglobulin superfamilies (IGSFs) and several members of tumor necrosis factor receptor (TNFR) superfamily are the major groups of T cell cosignaling molecules. The importance of these cosignaling pathways has been emphasized in a variety of human diseases, including graft versus host disease (GVHD), autoimmunity, infection, and cancer. Poliovirus receptor (PVR)-like proteins are a newly emerging group of IGSFs with T cell costimulatory functions. This group of molecules shares PVR-signature motif in the first immunoglobulin variable-like (IgV) domain, and are originally known to mediate epithelial cell-cell contacts. The two ligands, CD155 (PVR/Nec1-5) and CD112 (PVRL2/nectin-2), interact with CD226 (DNAM1) to costimulate T cells, and they also inhibit T cell response through another coinhibitory receptor, T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif [ITIM] domain (TIGIT). CD155 seems to be the predominant ligand in this ligand/receptor network because the interaction between CD112 and TIGIT is very weak. Adding to the complexity of this network CD155, but not CD112, interacts with CD96, another PVR-like protein present on T cells and natural killer (NK) cells, though the function of this interaction is still unclear. In addition, to its intrinsic inhibitory function, TIGIT exerts its T cell inhibitory effects through ligating CD155 on dendritic cells (DCs) to increase IL-10 secretion, or competes with the costimulatory receptor CD226 for ligand interaction.
Though the molecular and functional relationship between CD226 and TIGIT is still unclear, this novel cosignaling pathway represents important immunomodulators of T cell responses, as well as valuable targets for future immunotherapy. For instance, high TIGIT expression on CD8+ tumor-infiltrating lymphocytes (TILs) was observed in human tumor samples, and the ligands CD155 and CD122 were upregulated by the majority of APCs and cancer cells in the tumor microenvironment. TIGIT blockade synergized with PD-1 blockade to enhance CD8+ TIL activities both in mice and humans, and therefore rejected tumors in a transplanted mouse tumor model. Similarly, blockade of TIGIT and PD-L1 synergistically promoted anti-viral CD8+T cell response and therefore enhanced viral clearance in a inoculation of a soluble TIGIT fusion protein attenuated T cell-mediated response in a series of autoimmunity mouse models including, delayed-type hypersensitivity reactions (DTH), experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA).
The current disclosure relates to CD112R as a new coinhibitory receptor for human T cells. The present disclosure identifies CD112 as the ligand for CD112R.